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Preeclampsia An Update ARTICLE in ACTA A
Preeclampsia An Update ARTICLE in ACTA A
discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/271595737
Preeclampsia: An update
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Preeclampsia : an update
G. Lambert (*, **), J. F. Brichant (**), G. Hartstein (**), V. Bonhomme (*, **) and
P. Y. Dewandre (*, **)
Abstract : Preeclampsia was formerly defined as a mul- p atients. Antenatal corticosteroids should be adminis-
tisystemic disorder characterized by new onset of hyper- tered to less than 34 gestation week preeclamptic women
tension (i.e. systolic blood pressure (SBP) ≥ 140 mmHg to promote fetal lung maturity. Termination of pregnancy
and/or diastolic blood pressure (DBP) ≥ 90 mmHg) and should be discussed if severe preeclampsia occurs before
proteinuria (> 300 mg/24 h) arising after 20 weeks of 24 weeks of gestation. Maternal end organ dysfunction
gestation in a previously normotensive woman. Recent- and non-reassuring tests of fetal well-being are indica-
ly, the American College of Obstetricians and Gynecolo- tions for delivery at any gestational age. Neuraxial anal-
gists has stated that proteinuria is no longer required for gesia and anesthesia are, in the absence of thrombocyto-
the diagnosis of preeclampsia. This complication of penia, strongly considered as first line anesthetic
pregnancy remains a leading cause of maternal morbidity techniques in preeclamptic patients. Airway edema and
and mortality. tracheal intubation-induced elevation in blood pressure
Clinical signs appear in the second half of pregnancy, but are important issues of general anesthesia in those
initial pathogenic mechanisms arise much earlier. The patients. The major adverse outcomes associated with
cytotrophoblast fails to remodel spiral arteries, leading to preeclampsia are related to maternal central nervous
hypoperfusion and ischemia of the placenta. The fetal system hemorrhage, hepatic rupture, and renal failure.
consequence is growth restriction. On the maternal side, Preeclampsia is also a risk factor for developing cardio-
the ischemic placenta releases factors that provoke a gen- vascular disease later in life, and therefore mandates
eralized maternal endothelial dysfunction. The endothe- long-term follow-up.
lial dysfunction is in turn responsible for the symptoms
and complications of preeclampsia. These include hyper- Key words : Hemodynamic ; hypertension ; manage-
tension, proteinuria, renal impairment, thrombocytope- ment ; preeclampsia ; pregnancy.
nia, epigastric pain, liver dysfunction, hemolysis-elevat-
ed liver enzymes-low platelet count (HELLP) syndrome,
visual disturbances, headache, and seizures. Despite a
better understanding of preeclampsia pathophysiology
and maternal hemodynamic alterations during pre- Introduction
eclampsia, the only curative treatment remains placenta
and fetus delivery. Preeclampsia remains a leading cause of ma-
At the time of diagnosis, the initial objective is the ternal and fetal morbidity and mortality (1, 2). De-
assessment of disease severity. Severe hypertension spite a better understanding of its pathophysiology
(SBP ≥ 160 mm Hg and/or DBP ≥ 110 mmHg), throm- and some improvements in the ability of monitoring
bocytopenia < 100.000/µL, liver transaminases above
twice the normal values, HELLP syndrome, renal failure,
persistent epigastric or right upper quadrant pain, visual
or neurologic symptoms, and acute pulmonary edema are
G. Lambert, M.D. ; J.F. Brichant, Ph.D. ; G. Hartstein, M.D. ;
all severity criteria. Medical treatment depends on the se- V. Bonhomme, Ph.D. ; P. Y. Dewandre, M.D.
verity of preeclampsia, and relies on antihypertensive (*) University Department of Anesthesia & Intensive Care
medications and magnesium sulfate. Medical treatment Medicine, CHR de la Citadelle, Liege, Belgium.
does not alter the course of the disease, but aims at (**) Department of Anesthesia & Intensive Care Medicine,
CHU Liege, Belgium.
preventing the occurrence of intracranial hemorrhages
Correspondence address : Geraldine Lambert, University
and seizures. The decision of terminating pregnancy and Department of Anesthesia & ICM, CHR de la Citadelle,
perform delivery is based on gestational age, maternal 4000 Liège. Tel. : +32 42256111.
and fetal conditions, and severity of preeclampsia. Deliv- E-mail : glambert@chu.ulg.ac.be
ery is proposed for patients with preeclampsia without Funding and support : This review paper is in relation with
the 2012 SARB Grant awarded to the authors by the Society for
severe features after 37 weeks of gestation and in case of
Anesthesia and Resuscitation of Belgium.
severe preeclampsia after 34 weeks of gestation. Between This work was also supported by the Department of Anes-
24 and 34 weeks of gestation, conservative management thesia & Intensive Care Medicine, CHU Liege, Belgium. The
of severe preeclampsia may be considered in selected authors have no conflict of interest to disclose.
Table 1
Diagnostic criteria for preeclampsia (4)
Blood pressure • ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic on two occasions at least 4 hours apart after 20 weeks of
gestation in a woman with a previously normal blood pressure.
• ≥ 160 mmHg systolic or ≥ 110 mmHg diastolic can be confirmed within a short interval (minutes) to
facilitate timely antihypertensive therapy.
and
Proteinuria • ≥ 300 mg/24 h urine collection.
or
• Protein/creatinine ratio ≥ 0.3 (each measured as mg/dL).
• Dipstick reading of 1 + (if other methods not available).
Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following :
Thrombocytopenia • Platelet count < 100 000/µL
Renal insufficiency • Serum creatinine level > 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of
other renal disease.
Impaired liver function • Elevated blood concentrations of liver transaminases to twice normal concentration.
Pulmonary edema
Cerebral or visual symptoms
radiologic findings is in favor of the latter hypothe- lecular weight heparin (LMWH) have shown effi-
sis. Radiologic findings have been described as the cacy at preventing preeclampsia. Restriction of
posterior reversible encephalopathy syndrome dietary salt and restriction of physical activity in
(PRES). A recent study has evidenced PRES in al- addition to bed rest during pregnancy have no effect
most every eclamptic patient. Furthermore, PRES on preeclampsia prevention (4). Statins, by stimu-
has been identified in multiple areas of the brain in lating hemoxygenase expression, inhibit sFlt-1 re-
a series of cases where severe hypertension was not lease and promote VEGF. Studies to explore a pos-
a constant feature (25, 26). sible benefit of statins are currently being carried
out (9).
Several factors are associated with an in- The only etiologic treatment of preeclampsia
creased risk of preeclampsia : antiphospholipid syn- is fetus and placenta delivery. Timing of delivery
drome (risk ratio (RR) : 9.72), past history of pre- must take into account the gestational age, severity
eclampsia (RR : 7.19), pregestational diabetes of preeclampsia, as well as maternal and fetal con-
(RR :3.56), multiple gestation (RR : 2.93), nullipar- ditions. Current treatments aim at avoiding maternal
ity (RR : 2.91), family history of preeclampsia complications such as cerebral hemorrhage, pulmo-
(RR :2.90), body mass index (BMI) > 30 before nary edema, and eclampsia. Treatment is essentially
pregnancy (RR : 2.47), age ≥ 40 years (RR :1.96), based on antihypertensive therapy and magnesium
pre-existing hypertension (RR : 1.5), pre-existing sulfate (MgSO4).
renal disease, and pregnancy interval > 10 years (27, During the last 6 years, guidelines aiming at
28). Use of risk factors as predictive tools for pre- improving outcome of women with preeclampsia
eclampsia has only modest success. Biomarkers of have been published by several scientific societies.
preeclampsia and its severity have also been pro- They provide a robust common basis with minor
posed (8, 29). Placental expression and serum levels between-societies differences (4, 6, 7, 27, 32).
of sFlt-1 in preeclamptic women are increased dur- At the time of diagnosis, the initial objective is
ing active disease, as compared with normal preg- to assess the severity of the disease. In addition to
nancy. Serum levels of sFlt-1 are directly correlated blood pressure and proteinuria measurement and re-
with the severity of the disease. PlGF is low during cording, clinical signs of severity must be searched
preeclampsia. This is due to its binding to sFlt-1. A for. Neurological symptoms such as headache,
plasma sFlt-1/PlGF ratio ≥ 85 is associated with ad- blurred vision, or altered mental status must be con-
verse outcomes and delivery within two weeks of sidered, as well as epigastric pain or RUQ pain,
presentation (30). The sFlt-1/PlGF ratio could allow nausea and vomiting, oliguria, and dyspnea. Labo-
classifying the severity of the disease. Similarly, B- ratory evaluation must assess platelet count, schizo-
natriuretic peptide has been suggested as a marker cytes count, serum creatinine, liver transaminases,
of preeclampsia. Preeclamptic patients have higher bilirubin, LDH, haptoglobin, and coagulation tests.
levels of natriuretic peptide than non preeclamptic Fetal assessment relies on fetal heart rate, fetal
patients. Larger prospective studies are needed to weight, amniotic fluid volume, biophysical profile,
determine if elevated concentrations predict devel- and umbilical artery Doppler velocimetry.
opment of preeclampsia and its complications (31).
Up to now, the use of these biomarkers as parts of a a. Management of preeclampsia without severe
screening test remains investigational. features
Women at high risk of preeclampsia should re-
ceive low dose aspirin daily from gestation week 12 Recommendations for the management of pre-
to 37. Its prophylactic effect may be the result of the eclampsia without severe features before 37 weeks
inhibition of thromboxane production. Studies indi- of gestation are mainly based on expert opinion.
cate a small reduction in the incidence and morbid- Fluorinated steroids should be administered in pa-
ity of preeclampsia, with no difference in bleeding tients before 34 weeks of gestation, in order to favor
complication rates. Conversely, neither nutritional fetal maturation. Antihypertensive treatment re-
supplements (such as calcium, folic acid, vitamins mains controversial in patients with mild to moder-
C and E, fish oils, or garlic), nor drugs such as pro- ate hypertension (33). Prevention of eclampsia with
gesterone, nitric oxide donors, diuretics, or low mo- MgSO4 is not recommended in preeclamptic pa-
20 mmHg every 10 to 20 min has been suggested by in PC > 100.000/µL usually occurs at day 3 post
some authors (35). The most frequently recom- nadir, or day 6 postpartum.
mended medications for the treatment of severe
hypertension during pregnancy are hydralazine, e. Prevention and management of eclampsia
labetalol, calcium channel blockers and clonidine
(Table 5). Treatment of eclamptic seizures consists in the
Among antihypertensive medications that are administration of MgSO4 (Table 6), and in the treat-
considered to be safe in this context, no evidence ment of hypertension (Table 5). The Collaborative
supports one drug over another. Consequently, Eclampsia Trial showed a 67% reduction of recur-
choice should be based on the clinician’s experience rent seizures in eclamptic women treated with
and available resources. However, nitroprusside, di- MgSO4, as compared with those treated by phenyt-
azoxide, ketanserin, chlorpromazine should be oin. There was a 52% reduction in recurrence as
avoided. MgSO4 is not considered as an effective compared to diazepam. For women with eclampsia,
treatment for very high blood pressure (although MgSO4 should be continued for at least 24 hours
this is indicated for prevention and treatment of after the last seizure (39).
eclampsia) (36). Delivery is the only curative treatment. So far,
any other treatment is palliative. Expectant manage-
d. Management of HELLP syndrome ment of eclampsia to prolong gestation for fetal
benefit is associated with a substantial increase in
Corticosteroid administration to favor fetal maternal and perinatal morbidity and mortality. De-
maturation reverses HELLP-associated laboratory laying delivery for 24-48 hours in order to allow the
abnormalities in subgroup of patients, and might administration of corticosteroids prior to 34 gesta-
prolong pregnancy for 3-14 days. However, there is tion weeks has been reported in one retrospective
no evidence for a maternal or perinatal corticoste- study, but the safety of such an approach has not
roid-related improved outcome. Expectant manage- been proved. Induction of labor is sometimes pos-
ment of HELLP syndrome beyond 48 hours remains sible after maternal stabilization, and in case of an
an experimental approach, and is not recommend- expected delivery within 24 hours. Cesarean section
ed (37). Medical treatment of HELLP syndrome re- can be considered before 32 gestation weeks, or in
lies on antihypertensive treatment and MgSO4. case of unfavorable cervix. MgSO4 is the corner-
Platelet transfusion should be considered if PC falls stone of the prevention and treatment of eclampsia.
below 20.000/µL, in case of bleeding, and to achieve Its use is associated with a 50% reduction of ec-
a PC of 40-50.000/µL in case of caesarean sec- lampsia episodes in severe preeclampsia. It also re-
tion (6). Randomized controlled trials have provid- duces the risk of maternal death. The number need-
ed evidence of improvement in platelet count with ed to treat (NNT) to observe 1 beneficial effect is 50
corticosteroids, but no improved overall maternal for severe preeclampsia patients, whereas it rises to
outcome. In clinical settings where an improvement 100 for patients with preeclampsia without severe
of platelet count is considered useful, corticoste- features (40). In case of severe preeclampsia arising
roids could be used (38). Worsening of hemolysis, in the postpartum period, the administration of
thrombocytopenia, and liver dysfunction is com- MgSO4 is also recommended for at least 24 hours.
mon during the first 24-48 postpartum hours. A rise The effect of MgSO4 is likely multifactorial, includ-
HELLP syndrome before fetal viability is an usually considered safe for neuraxial techniques.
indication of delivery, shortly after maternal stabili- Some authors consider a platelet count of 50.000/
zation. When those patients are at or beyond 34 ges- µL as acceptable for spinal anesthesia (32).
tation weeks, it is recommended to proceed to deliv-
ery soon after initial maternal stabilization. In b. Neuraxial analgesia for labor
between gestational age of fetal viability and 33 6/7
gestation weeks, it is suggested to delay delivery for Unless contraindicated, preeclampsia is con-
24-48 hours, but only if maternal and fetal condi- sidered to be a medical indication for epidural or
tions remain stable and allow completing a course combined spinal epidural analgesia (CSE) during
of corticosteroids for fetal benefits. labor. These techniques not only provide optimal
analgesia, but also give better maternal hemo
h. Mode of delivery dynamic control. In addition, an in situ epidural
catheter during labor may avoid the risks associated
For women with preeclampsia, the mode of with general anesthesia, should an emergency
delivery should be determined by the fetal gesta- cesarean section become necessary during labor.
tional age, fetal presentation, cervical status, and
maternal and fetal condition. Caesarean delivery is c. Neuraxial anesthesia for cesarean delivery
therefore not mandatory. Cervix ripening with in-
duction of labor should be considered when possi- Unless contraindicated, neuraxial anesthesia is
ble. After 32 gestation weeks, a 60% vaginal birth the technique of choice for cesarean delivery. Neur-
rate is achievable (46). axial anesthesia provides satisfactory hemodynamic
stability, and avoids the risks associated with gen-
eral anesthesia in preeclamptic patients. These risks
Anesthesia and analgesia for the preeclamptic include the potential presence of a difficult airway,
parturient and severe hypertension associated with tracheal
intubation. For many years, the fear of profound
a. Coagulopathy and regional techniques hypotension caused by the sympathetic blockade in
patients with increased vascular resistance and
The risk of spinal hematoma associated with a depleted intravascular volume precluded the use of
coagulopathy has always been a concern in pre- spinal anesthesia, and favored the use of epidural
eclamptic women. Preeclampsia is associated with anesthesia. However, numerous studies have dem-
an increased incidence of thrombocytopenia, and onstrated that spinal anesthesia in preeclamptic
potentially other coagulation abnormalities. On the women is associated with less hypotension, less
other hand, spinal hematoma is less frequent in par- vasopressor requirement, and minimal changes in
turient women as compared to the general popula- CO (51-53). It has also been demonstrated that re-
tion. The very few cases reported in obstetrics are gional anesthesia for cesarean section in preeclamp-
associated with HELLP syndrome (47). Several tic women is associated with a two times higher
studies have addressed the incidence of thrombocy- stroke-free survival rate, as compared to general
topenia and coagulopathy in preeclampsia, and anesthesia (54). Therefore, spinal anesthesia can be
demonstrate a maximal 10% incidence of thrombo- safely used in this population (55). Combined spi-
cytopenia (< 100.000/µL) in preeclamptic patients. nal-epidural anesthesia is also an appropriate tech-
Increase in prothrombin time (PT), partial thrombo- nique for these patients (56). Epidural anesthesia is
plastin time (PTT), or decreased fibrinogen have the technique of choice when a cesarean section is
only been described in severe preeclampsia associ- required during labor under epidural analgesia.
ated with a thrombocytopenia below 100.000/µL.
These data lead to the conclusion that, in preeclamp- d. General anesthesia for cesarean section
sia, the sole monitoring of platelet count, and re-
serving PT, PTT and fibrinogen monitoring for pa- In case of contraindications to neuraxial
tients with thrombocytopenia, is a safe policy (48, anesthesia (i.e. pulmonary edema, coagulopathy, al-
49). Guidelines suggest that monitoring platelet tered consciousness following eclamptic seizures),
count in preeclamptic patients (as opposed to nor- general anesthesia may be required for cesarean de-
mal pregnancy) reduces maternal anesthesia com- livery. General anesthesia may lead to several diffi-
plications (50). A stable platelet count > 75.000/µL culties. Intubation can be complicated by airway
in the absence of other coagulation abnormalities is edema, while a severe hypertensive response may
Table 7
Example of treatment of postpartum hypertension
Drug Dose Action Contra-indications Secondary effects
Nifedipine 20-120 mg/d Calcium channel antagonist Aortic stenosis Headache, flushing, tachycardia
Oral labetalol 200-1200 mgL/d in two or β-blocker with vascular Asthma Bradycardia, bronchospasm,
three didvides doses α-receptor blocking abiblty headache, nausea
Propanolol 120-240 mg/d in three β-blocker Asthma Bradycardia, bronchospasm, nausea
divided doses
Captopril 50 mg/d in two divided ACE inhibitor Pregnancy, renal artery Hyperkaliemia, angioneurotic
doses stenosis edema, reduced lactation?